1. INTRODUCTION
These
guidelines outline the general principles and approaches that FDA considers
appropriate elements of process validation for the manufacture of active
pharmaceutical ingredients (APIs or drug substances). These guidelines
incorporate principles and approaches that all manufacturers can use to
validate manufacturing processes.
FDA
encourages the use of modern pharmaceutical development concepts, quality risk
management, and quality systems at all stages of the manufacturing process
lifecycle.
The
lifecycle concept links product and process development, qualification of the commercial
manufacturing process, and maintenance of the process in a state of control
during routine commercial production. These guidelines support process
improvement and innovation through sound science.
These guidelines cover the following
categories of drugs:
·
Human drugs
·
Veterinary drugs
·
Biological and biotechnology
products
·
Finished products and active
pharmaceutical ingredients (APIs or drug substances)
These guidelines do not cover the
following types of products:
·
Type A medicated articles and
medicated feed
·
Medical devices
·
Dietary supplements
·
Human tissues intended for
transplantation regulated under section 361 of the Public Health Service Act.
·
These
guidelines are relevant, however, to the validation of processes that include
automated equipment in processing.
Process Validation and Drug Quality
Effective
process validation contributes significantly to assuring drug quality. The
basic principle of quality assurance is that a drug should be produced that is
fit for its intended use. This principle
incorporates the understanding that the following conditions exist:
·
Quality, safety, and efficacy are
designed or built into the product.
·
Quality cannot be adequately assured
merely by in-process and finished-product inspection or testing.
·
Each step of a manufacturing process
is controlled to assure that the finished product meets all quality attributes
including specifications.
2. Approach to Process Validation
For
purposes of these guidelines, “Process
Validation “is defined as the collection and evaluation of data, from the
process design stage through commercial production, which establishes
scientific evidence that a process is capable of consistently delivering
quality product. Process validation involves a series of activities taking
place over the lifecycle of the product and process.
These
guidelines describe process validation activities in three stages:
·
Stage
1 – Process Design: The commercial
manufacturing process is defined during this stage based on knowledge gained
through development and scale-up activities.
·
Stage
2 – Process Qualification: During
this stage, the process design is evaluated
to determine if the process is capable of reproducible commercial manufacturing.
· Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control.
These
guidelines describe activities typical of each stage, but in practice, some
activities might occur in multiple stages.
Before
any batch from the process is commercially distributed for use by consumers, a
manufacturer should have gained a high degree of assurance in the performance
of the manufacturing process such that it will consistently produce APIs and
drug products meeting those attributes relating to identity, strength, quality,
purity, and potency.
The
assurance should be obtained from objective information and data from
laboratory-, pilot-, and commercial- scale studies.
Information
and data should demonstrate that the commercial manufacturing process is
capable of consistently producing acceptable quality products within commercial
manufacturing conditions.
Manufacturers
should:
·
Understand the sources of variation
·
Detect the presence and degree of variation
·
Understand the impact of variation
on the process and ultimately on product attributes
·
Control the variation in a manner
commensurate with the risk it represents to the process and product.
Each
manufacturer should judge whether it has gained sufficient understanding to
provide a high degree of assurance in its manufacturing process to justify
commercial distribution of the product.
Focusing
exclusively on qualification efforts without also understanding the
manufacturing process and associated variations may not lead to adequate
assurance of quality.
After
establishing and confirming the process, manufacturers must maintain the process
in a state of control over the life of the process, even as materials,
equipment, production environment, personnel, and manufacturing procedures
change.
Manufacturers
should use ongoing programs to collect and analyze product and process data to
evaluate the state of control of the process.
These
programs may identify process or product problems or opportunities for process
improvements.
Manufacturers
of legacy products can take advantage of the knowledge gained from the original
process development and qualification work as well as manufacturing experience
to continually improve their processes.
3. STATUTORY AND REGULATORY
REQUIREMENTS FOR PROCESS VALIDATION
Process validation for finished
pharmaceuticals is a legally enforceable requirement under section 501(a) (2) (B)
of the Act (21 U.S.C. 351(a) (2) (B)), which states the following:
A drug shall be deemed to
be adulterated if the methods used in, or the facilities or controls used for,
its manufacture, processing, packing, or holding do not conform to or are not
operated or administered in conformity with current good manufacturing practice
to assure that such drug meets the requirements of this Act as to safety and
has the identity and strength, and meets the quality and purity
characteristics, which it purports or is represented to possess.
The
CGMP regulations require that manufacturing processes be designed and
controlled to assure that in-process materials and the finished product meet
predetermined quality requirements and do so consistently and reliably. Process
validation is required, in both general and specific terms.
The
foundation for process validation states that the drug products have the
identity, strength, quality, and purity they purport or are represented to
possess.”
This
regulation requires manufacturers to design a process, including operations and
controls, which results in a product meeting these attributes.
Other CGMP regulations define the
various aspects of validation.
For
example, Sampling and testing of in-process materials and drug products,
requires that control procedures “be established to monitor the output and to
validate the performance of
those manufacturing processes that may be responsible for causing variability
in the characteristics of in-process material and the drug product”.
Under
this regulation, even well-designed processes must include in-process control
procedures to assure final product quality.
In
addition, the CGMP regulations regarding sampling set forth a number of
requirements for validation: samples must represent the batch under analysis,
the sampling plan must result in statistical confidence and the batch must meet
its predetermined specifications.
In
addition to sampling requirements, the CGMP regulations also provide norms for
establishing in-process specifications as an aspect of process validation.
FDA
establishes two principles to follow when establishing in-process
specifications.
The first principle is that:
“in-process specifications for such characteristics of in-process drug
material shall be consistent with drug product final specifications”.
Accordingly, in-process material should be controlled to assure that the final
drug product will meet its quality requirements.
The second principle: in this regulation further
requires that “in-process specifications shall be derived from previous
acceptable process average and process variability estimates where possible and
determined by the application of suitable statistical procedures where appropriate.”
This requirement, in part, establishes the need for manufacturers to analyze
process performance and control batch-to-batch variability.
FDA also describes
and defines activities connected with process design, development, and
maintenance. Ongoing feedback about product quality and process performance is
an essential feature of process maintenance.
In
addition, the FDA regulations require that facilities in which drugs are
manufactured be of suitable size, construction, and location to facilitate proper
operations.
Equipment must be of appropriate design,
adequate size, and suitably located to facilitate operations for its intended
use.
Automated, mechanical, and electronic
equipment must be calibrated, inspected, or checked according to a written
program designed to assure proper performance
In summary, the FDA regulations
require that manufacturing processes be designed and controlled to assure that
in-process materials and the finished product meet predetermined quality
requirements and do so consistently and reliably.
4. RECOMMENDATIONS
In the
following sections, we describe general considerations for process validation,
the recommended stages of process validation, and specific activities for each
stage in the product lifecycle.
A.
General
Considerations for Process Validation
In all
stages of the product lifecycle, the following practices should ensure uniform
collection and assessment of information about the process and enhance the
accessibility of such information later in the product lifecycle.
·
We recommend an integrated team
approach to
process validation that includes expertise from a variety of disciplines (e.g.,
Engineering department, Production department, Quality Control department, and
Quality Assurance department).
·
Throughout the product lifecycle,
various studies can be initiated to discover, observe, correlate, or confirm
information about the product and process. All studies should be planned and
conducted according to sound scientific principles, appropriately documented,
and approved in accordance with the established procedure appropriate for the
stage of the lifecycle.
·
The terms attributes (e.g., quality, product, component) and
parameters (e.g., process, operating, and
equipment) are not categorized with respect to criticality in these guidelines.
·
With a lifecycle approach to process
validation that employs risk based decision making throughout that lifecycle,
the perception of criticality as a continuum rather than a binary state is more
useful.
·
All attributes and parameters should
be evaluated in terms of their roles in the process and impact on the product
or in-process material, and reevaluated as new information becomes available.
·
The degree of control over those
attributes or parameters should be commensurate with their risk to the process
and process output.
· In other words, a higher degree of control is appropriate for attributes or parameters that pose a higher risk.
·
Many products are single-source or
involve complicated manufacturing processes.
·
Homogeneity within a batch and
consistency between batches are goals of process validation activities.
·
Validation offers assurance that a
process is reasonably protected against sources of variability that could affect
production output, cause
supply problems, and
negatively affect public health.
B.
Stage
1 ― Process Design
Process
design is the activity of defining the commercial manufacturing process that
will be reflected in planned master production and control records.
The goal
of this stage is to design a process suitable for routine commercial
manufacturing that can consistently deliver a product that meets its quality
attributes.
Building and Capturing Process Knowledge and Understanding
Generally,
early process design experiments do not need to be performed under the CGMP
conditions required for drugs intended for commercial distribution that are
manufactured during Stage 2 (process qualification) and Stage 3 (continued
process verification).
They
should, however, be conducted in accordance with sound scientific methods and
principles, including good documentation practices.
This
recommendation is consistent with ICH Pharmaceutical Quality System.
Decisions
and justification of the controls should be sufficiently documented and
internally reviewed to verify and preserve their value for use or adaptation
later in the lifecycle of the process and product.
Product
development activities provide key inputs to the process design stage, such as
the intended dosage form, the quality attributes, and a general manufacturing
pathway.
Process
information available from product development activities can be leveraged in
the process design stage.
The
functionality and limitations of commercial manufacturing equipment should be
considered in the process design, as well as predicted contributions to
variability posed by different component lots, production operators,
environmental conditions, and measurement systems in the production setting.
However,
the full spectrum of input variability typical of commercial production is not
generally known at this stage.
Laboratory
or pilot-scale models designed to be representative of the commercial process
can be used to estimate variability.
Design of Experiment (DOE) studies can help develop process
knowledge by revealing relationships, component characteristics or
process parameters and the in-process material or the final product.
Risk
analysis tools can be used to screen potential variables for DOE studies to
minimize the total number of experiments conducted while maximizing knowledge
gained.
The
results of DOE studies can provide justification for establishing ranges of
incoming component quality, equipment parameters, and
in-process material quality attributes.
FDA does
not generally expect manufacturers to develop and test the process until it
fails.
Other
activities, such as experiments or demonstrations at laboratory or pilot scale,
also assist in evaluation of certain conditions and prediction of performance
of the commercial process.
These
activities also provide information that can be used to model or simulate the
commercial process.
It is
essential that activities and studies resulting in process understanding be
documented. Documentation should reflect the basis for decisions made about the
process.
This
information is useful during the process qualification and continued process
verification stages, including when the design is revised or the strategy for
control is refined or changed.
Establishing a Strategy for Process Control
Strategies
for process control can be designed to reduce input variation, adjust for input
variation during manufacturing (and so reduce its impact on the output), or
combine both approaches.
Process
controls address variability to assure quality of the product.
Controls
can consist of material analysis and equipment monitoring at significant
processing points.
Decisions regarding the type and extent of process controls can be aided by earlier risk assessments, then enhanced and improved as process experience is gained.
FDA
expects controls to include both examination of material quality and equipment
monitoring. Special attention to control the process through operational limits
and in-process monitoring is essential in two possible scenarios:
1.
When the product attribute is not
readily measurable due to limitations of sampling or detectability (e.g. microbial
contamination) or
2.
When intermediates and products
cannot be highly characterized and well-defined quality attributes cannot be
identified.
More
advanced strategies, which may involve the use of process analytical technology (PAT), can include timely analysis
and control loops to adjust the processing conditions so that the output
remains constant.
Manufacturing
systems of this type can provide a higher degree of process
control than non-PAT systems.
In the
case of a strategy using PAT, the approach to process qualification will differ
from that used in other process designs.
The
planned commercial production and control records, which contain the
operational limits and overall strategy for process control, should be carried
forward to the next stage for confirmation.
Stage
2 ― Process Qualification
During
the process qualification (PQ) stage of process validation, the process design
is evaluated to determine if it is capable of reproducible commercial
manufacture.
This stage has two elements:
1. Design of the facility and
qualification of the equipment and utilities
2. Process performance qualification
(PPQ).
During
Stage 2, CGMP-compliant procedures must be followed.
Successful
completion of Stage 2 is necessary before commercial distribution.
Products
manufactured during this stage, if acceptable, can be released for distribution.
Design of a Facility and Qualification of Utilities and Equipment
Proper
design of a manufacturing facility is required under CGMP regulations on buildings
and facilities.
It is
essential that activities performed to assure proper facility design and
commissioning precede PPQ. Here, the term
Qualification refers to activities undertaken to demonstrate that utilities and
equipment are suitable for their intended use and perform properly.
These
activities necessarily precede manufacturing products at the commercial scale.
Qualification of utilities and
equipment generally includes the following activities:
·
Selecting
utilities and equipment construction materials,
operating principles and performance characteristics based on whether they are
appropriate for their specific uses.
·
Verifying
that utility systems and equipment are built and installed
in compliance with the design specifications (e.g., built as designed with
proper materials, capacity, and functions, and properly connected and calibrated).
·
Verifying
that utility systems and equipment operate in
accordance with the process requirements in all anticipated operating ranges.
This
should include challenging the equipment or system functions while under load
comparable to that expected during routine production.
It should also include the performance of
interventions, stoppage, and start-up as is expected during routine production.
Operating ranges should be shown capable of being held
as long as would be necessary during routine
production.
Qualification
of utilities and equipment can be covered under individual plans or as part of
an overall project plan.
The plan
should consider the requirements of use and can incorporate risk management to
prioritize certain activities and to identify a level of effort in both the
performance and documentation of qualification activities.
The plan should identify the following items:
1. The
studies or tests to use,
2. The
criteria appropriate to assess outcomes,
3.
The timing of qualification activities,
4.
The responsibilities of relevant
departments and the quality unit, and
5. The
procedures for documenting and approving the
qualification.
The
project plan should also include the firm’s requirements for the evaluation of
changes.
Qualification
activities should be documented and summarized in a report with conclusions
that address criteria in the plan. The quality control unit must review and
approve the qualification plan and report.
Process Performance
Qualification
The
process performance qualification (PPQ) is the second element of Stage 2,
process qualification.
The PPQ
combines the actual facility, utilities, equipment (each now qualified), and
the trained personnel with the commercial manufacturing process, control
procedures, and components to produce commercial batches.
A
successful PPQ will confirm the process design and demonstrate that the
commercial manufacturing process performs as expected.
Success
at this stage signals an important milestone in the product lifecycle.
A
manufacturer must successfully complete PPQ before commencing commercial
distribution of the drug product.
The
decision to begin commercial distribution should be supported by data from
commercial-scale batches. Data from laboratory and pilot studies can provide
additional assurance that the commercial manufacturing process performs as
expected.
The
approach to PPQ should be based on sound science and the manufacturer’s overall
level of product and process understanding and demonstrable control.
The
cumulative data from all relevant studies (e.g., designed experiments;
laboratory, pilot, and commercial batches) should be used to establish the
manufacturing conditions in the PPQ.
To
understand the commercial process sufficiently, the manufacturer will need to
consider the effects of scale. However, it is not typically necessary to
explore the entire operating range at commercial scale if assurance can be
provided by process design data.
Previous
credible experience with sufficiently similar products and processes can also
be helpful.
In
addition, we strongly recommend firms employ objective
measures (e.g., statistical metrics) wherever feasible and meaningful to
achieve adequate assurance.
In most
cases, PPQ will have a higher level of sampling, additional testing, and
greater scrutiny of process performance than would be typical of routine
commercial production.
The level
of monitoring and testing should be sufficient to confirm uniform product
quality throughout the batch.
The
increased level of scrutiny, testing, and sampling should continue through the
process verification stage as appropriate, to establish levels and frequency of
routine sampling and monitoring for the particular product and process.
Considerations
for the duration of the heightened sampling and monitoring period could
include, but are not limited to, volume of production, process complexity,
level of process understanding, and experience with similar products and
processes.
The
extent to which some materials, such as column resins or molecular filtration
media, can be re-used without adversely affecting product quality can be
assessed in relevant laboratory studies.
The
usable lifetimes of such materials should be confirmed by an ongoing PPQ
protocol during commercial manufacture.
A
manufacturing process that uses PAT may warrant a different PPQ approach.
PAT
processes are designed to measure in real time the attributes of an in-process
material and then adjust the process in a timely control loop so the process
maintains the desired quality of the output material.
The process design stage and the process qualification stage should focus on the measurement system and control loop for the measured attribute.
Regardless,
the goal of validating any manufacturing process is the same: to establish
scientific evidence that the process is reproducible and will consistently
deliver quality products.
A written
protocol that specifies the manufacturing conditions, controls, testing, and
expected outcomes is essential for this stage of process validation. We
recommend that the protocol discuss the following elements:
·
The
manufacturing conditions, including operating parameters,
processing limits, and component (raw material) inputs.
·
The data to be collected and when and how it will be evaluated.
·
Tests
to be performed (in-process, release,
characterization) and acceptance criteria for each significant processing step.
·
The
sampling plan, including sampling points, number of
samples, and the frequency of sampling for each unit operation and attribute.
·
The
number of samples should be adequate to provide
sufficient statistical confidence of quality both within a batch and between
batches.
·
The confidence level selected can be
based on risk analysis as it relates to the particular attribute under
examination.
·
Sampling during this stage should be more
extensive than is typical during routine production.
·
Criteria
and process performance indicators that allow for a
science- and risk-based decision about the ability of the process to
consistently produce quality products. The criteria should include:
·
A description of the statistical
methods to be used in analyzing all collected data (e.g., statistical metrics
defining both intra-batch and inter-batch variability).
·
Provision for addressing deviations
from expected conditions and handling of nonconforming data. Data should not be
excluded from further consideration in terms of PPQ without a documented,
science-based justification.
·
Design of facilities and the qualification of
utilities and equipment, personnel training and qualification, and verification
of material sources (components and container/closures), if not previously accomplished.
·
Status of the validation of
analytical methods used in measuring the process, in- process materials, and
the product.
·
Review and approval of the protocol
by appropriate departments and the quality unit.
PPQ Protocol Execution and Report
Execution
of the PPQ protocol should not begin until the protocol has been reviewed and
approved by all appropriate departments, including the quality unit.
Any
departures from the protocol must be made according to established procedure or
provisions in the protocol.
Such
departures must be justified and approved by all appropriate departments and
the quality unit before implementation.
The
commercial manufacturing process and routine procedures must be followed during
PPQ protocol execution.
The PPQ
lots should be manufactured under normal conditions by the personnel routinely
expected to perform each step of each unit operation in the process.
Normal
operating conditions should include the utility systems (e.g., air handling and
water purification), material, personnel, environment, and manufacturing
procedures.
A report documenting and assessing adherence to the written PPQ protocol should be prepared in a timely manner after the completion of the protocol.
This report should:
·
Discuss and cross-reference all
aspects of the protocol.
·
Summarize data collected and analyze
the data, as specified by the protocol.
·
Evaluate any unexpected observations
and additional data not specified in the protocol.
·
Summarize and discuss all
manufacturing non-conformances such as deviations, abnormal test results, or
other information that has bearing on the validity of the process.
·
Describe corrective actions or
changes that should be made to
existing procedures and controls.
·
State a clear conclusion as to
whether the data indicates the process met the conditions established in the
protocol and whether the process is considered to be in a state of control.
·
If not, the report should state what
should be accomplished before such a conclusion can be reached.
·
This conclusion should be based on a
documented justification for the approval of the process, and release of lots
produced by it to the market in consideration of the entire compilation of
knowledge and information gained from the design stage through the process
qualification stage.
·
Include all appropriate department
and quality unit review and approvals.
Stage 3 ― Continued Process Verification
The
goal of the third validation stage is continual assurance that the process
remains in a state of control (the validated state) during commercial
manufacture.
A
system or systems for detecting unplanned departures from the process as
designed is essential to accomplish this goal.
Adherence
to the CGMP requirements, specifically, the collection and evaluation of
information and data about the performance of the process, will allow detection
of undesired process variability.
Evaluating
the performance of the process identifies problems and determines whether
action must be taken to correct, anticipate, and prevent problems so that the
process remains in control.
An
ongoing program to collect and analyze product and process data that relate to
product quality must be established.
The data
collected should include relevant process trends and quality of incoming
materials or components, in-process material, and finished products.
The data
should be statistically trended and reviewed by trained personnel.
The
information collected should verify that the quality attributes are being
appropriately controlled throughout the process.
We
recommend that a statistician or person with adequate training in statistical
process control techniques develop the data collection plan and statistical
methods and procedures used in measuring and evaluating process stability and
process capability. Procedures should describe how
trending and calculations are to be performed and should guard against
overreaction to individual events as well as against failure to detect
unintended process variability.
Production
data should be collected to evaluate process stability and capability. The
quality unit should review this information. If properly carried out, these
efforts can identify variability in the process and/or signal potential process
improvements.
Good
process design and development should anticipate significant sources of
variability and establish appropriate detection, control, and/or mitigation
strategies, as well as appropriate alert and action limits. However, a process
is likely to encounter sources of variation that were not previously detected
or to which the process was not previously exposed.
Many
tools and techniques, some statistical and others more qualitative, can be used
to detect variation, characterize it, and determine the root cause.
We
recommend that the manufacturer use quantitative, statistical methods whenever
appropriate and feasible.
Scrutiny of intra-batch as well as inter-batch variation is part of a comprehensive continued process verification program.
We
recommend continued monitoring and sampling of process parameters and quality
attributes at the level established during the process qualification stage
until sufficient data are available to generate significant variability
estimates.
These
estimates can provide the basis for establishing levels and frequency of
routine sampling and monitoring for the particular product and process.
Monitoring
can then be adjusted to a statistically appropriate and representative level.
Process
variability should be periodically assessed and monitoring adjusted
accordingly.
Variation
can also be detected by the timely assessment of defect complaints, out-of-
specification findings, process deviation reports, process yield variations,
batch records, incoming raw material records, and adverse event reports.
Production
line operators and quality unit staff should be encouraged to provide feedback
on process performance.
We
recommend that the quality unit meet periodically with production staff to
evaluate data, discuss possible trends or undesirable process variation, and
coordinate any correction or follow-up actions by production.
Data
gathered during this stage might suggest ways to improve and/or optimize the
process by altering some aspect of the process or product, such as the
operating conditions (ranges and set- points), process controls, component, or
in-process material characteristics.
A
description of the planned change, a well-justified rationale for the change,
an implementation plan, and quality unit approval before implementation must be
documented.
Depending
on how the proposed change might affect product quality, additional process
design and process qualification activities could be warranted.
Maintenance
of the facility, utilities, and equipment is another important aspect of
ensuring that a process remains in control. Once established, qualification
status must be maintained through routine monitoring, maintenance, and
calibration procedures and schedules.
The
equipment and facility qualification data should be assessed periodically to
determine whether re-qualification should be performed and the extent of that
re-qualification.
Maintenance
and calibration frequency should be adjusted based on feedback from these
activities.
5. CONCURRENT RELEASE OF PPQ BATCHES
In most
cases, the PPQ study needs to be completed successfully and a high degree of
assurance in the process achieved before commercial distribution of a product.
In
special situations, the PPQ protocol can be designed to release a PPQ batch for
distribution before complete execution of the protocol steps and activities,
i.e., concurrent release. FDA expects that concurrent release will be used
rarely.
Conclusions
about a commercial manufacturing process can only be made after the PPQ
protocol is fully executed and the data are fully evaluated.
If Stage
2 qualification is not successful (i.e., does not demonstrate that the process
as designed is capable of reproducible performance at commercial scale), then
additional design studies and qualification may be necessary.
The new
product and process understanding obtained from the unsuccessful qualification
studies can have negative implications if any lot was already distributed.
Full execution of Stages 1 and 2 of process
validation is intended to preclude or minimize that outcome.
Circumstances
and rationale for concurrent release should be fully described in the PPQ
protocol.
Even when
process performance assessment based on the PPQ protocol is still outstanding,
any lot released concurrently must comply with all CGMPs, regulatory approval
requirements, and PPQ protocol lot release criteria.
Lot
release under a PPQ protocol is based upon meeting confidence levels
appropriate for each quality attribute of the drug.
When warranted and used, concurrent release should be accompanied by a system for careful oversight of the distributed batch to facilitate rapid customer feedback.
For
example, customer complaints and defect reports should be rapidly assessed to
determine root cause and whether the process should be improved or
changed.
Concurrently
released lots must also be assessed in light of any negative PPQ study finding
or conclusions and appropriate corrective action must be taken.
We
recommend that each batch in a concurrent release program be evaluated for
inclusion in the stability program. I
t is
important that stability test data be promptly evaluated to ensure rapid
detection and correction of any problems.
6. DOCUMENTATION
Documentation
at each stage of the process validation lifecycle is essential for effective
communication in complex, lengthy, and multidisciplinary projects.
Documentation
is important so that knowledge gained about a product and process is accessible
and comprehensible to others involved in each stage of the lifecycle.
Information transparency and accessibility are fundamental tenets of the
scientific method.
They are
also essential to enabling organizational units responsible and accountable for
the process to make informed, science-based decisions that ultimately support
the release of a product to commerce.
The
degree and type of documentation required by CGMP vary during the validation
lifecycle. Documentation requirements are greatest during Stage 2, process
qualification, and Stage 3, continued process verification.
Studies
during these stages must conform to CGMP and must be approved by the quality
unit in accordance with the regulations.
CGMP
documents for commercial manufacturing (i.e., the initial commercial master
batch production and control record and supporting procedures) are key outputs
of Stage 1, process design.
We
recommend that firms diagram the process flow for the full-scale process.
Process
flow diagrams should describe each unit operation, its placement in the overall
process, monitoring and control points, and the component, as well as other
processing material inputs (e.g., processing aids) and expected outputs (i.e.,
in-process materials and finished product).
It is
also useful to generate and preserve process flow diagrams of the various
scales as the process design progresses to facilitate comparison and decision
making about their comparability.
7. ANALYTICAL METHODOLOGY
Process
knowledge depends on accurate and precise measuring techniques used to test and
examine the quality of drug components, in-process materials, and finished
products.
Validated
analytical methods are not necessarily required during product- and process-development
activities or when used in characterization studies.
Nevertheless,
analytical methods should be scientifically sound (e.g., specific, sensitive,
and accurate) and provide results that are reliable.
There
should be assurance of proper equipment function for laboratory experiments.
Procedures
for analytical method and equipment maintenance, documentation practices, and
calibration practices supporting process-development efforts should be
documented or described.
New
analytical technology and modifications to existing technology are continually
being developed and can be used to characterize the process or the product.
Use of
these methods is particularly appropriate when they reduce risk by providing
greater understanding or control of product quality.